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A 2015 epidemiological study raised eyebrows when it claimed that people with the lowest body weight ran the highest risk of Alzheimer’s disease. The observation seemed to fly in the face of multiple independent reports linking midlife obesity to a greater risk of developing the disease later on. The study did not address cause and effect, leading critics to point out that the low body weight might indeed have been caused by the disease, not the other way around.

A new study ... lends credence to this interpretation. Researchers ... looked for a link between Alzheimer’s disease and genetically determined body weight [based on Mendelian randomization, using the "five genes that have been shown to have the strongest effects on body mass: FTO, MC4R, TMEM18, BDNF, and GNPDA2] in cohorts totaling about 400,000 people. They found no relationship, suggesting that body weight by itself does not affect AD risk.

Weight loss during early stages of this slowly developing disease may explain the apparent higher AD incidence among thinner people, Frikke-Schmidt suggested. ...

To try to clarify the role of body weight in AD, first author Liv Tybjærg Nordestgaard analyzed 95,578 participants in the Copenhagen General Population Study. Over a period of 37 years, 645 of them were diagnosed with AD. When Nordestgaard and colleagues stratified this population by body mass index (BMI), they saw the same association found in the U.K. study—those in the lowest-weight quartile ran about twofold the risk of AD as the heaviest participants.

Did low weight bring on the disease? The authors picked five genes that have been shown to have the strongest effects on body mass ... They reasoned that any linkage between variants that keep people slim and Alzheimer’s disease would support a causal effect of low BMI. Such Mendelian randomization studies approximate a randomized clinical trial, ...

In contrast to the observational data, common genetic variants that lead to low, or even high, BMI did not budge the risk of AD. To confirm BMI has no effect, the authors also analyzed data from two large genetic consortia, the Genetic Investigation of Anthropometric Traits (GIANT) and the International Genomics of Alzheimer’s Project (IGAP), which together comprise 303,958 participants. In these cohorts, the researchers looked at 32 genetic variants that influence body mass, and again saw no relationship to Alzheimer’s.

As a positive control, the researchers looked for a link between BMI and the risk of Type 2 diabetes. ... [V]ariants that lower BMI protected against diabetes in the Copenhagen cohort.

If lifelong body mass does not affect AD, what explains the higher rates of diagnosis observed among those with low BMI? Frikke-Schmidt noted two main possibilities. Either a confounding factor—something associated with low BMI—is the true source of AD risk, or reverse causality is at play, i.e. the AD itself causes the weight loss. Based on other evidence, Frikke-Schmidt considers the second idea most likely. “We know changes happen in the brain before an overt diagnosis of AD, and these may affect appetite,” she said.

Supporting this, an April 27 Scientific Reports paper ... analyzed cross-sectional data from 120 cognitively healthy people who carry familial AD mutations and 110 non-carriers ... They saw lower BMIs among carriers than non-carriers as early as 18 years before expected symptom onset. The difference was greater the closer people approached expected symptom onset, becoming significant 11 years prior. “Taking these findings together, it seems most likely that body mass decline is not a risk factor, but an early symptom in the preclinical stage of AD,” Laske wrote to Alzforum. He said BMI seems to decline even earlier than cognition in familial AD.

This does not explain why other studies have found a link between midlife obesity and dementia. Frikke-Schmidt noted that many of those studies looked at all-cause dementia, rather than AD specifically. She speculated that obesity may contribute to vascular dementia, mixed dementia, and AD through vascular mechanisms (see Jul 2016 news). These likely include diabetes and hypertension, both of which are known risk factors for Alzheimer’s.

We were also puzzled about the apparent increased dementia risk for those with low BMI, and have written about this in a correspondence letter in Lancet Diabetes & Endocrinology in 2015 (see Strand et al., 2015).

We followed this up in a full paper, recently published in the Journals of Gerontology,... (Strand et al., 2017). ...

Thus, the increased AD risk for those with low BMI in several observational studies might be due to reverse causality. Their results fit with ours; those with stable low BMI through midlife (35-62 years) were not at increased risk of dementia-related mortality, while only those with decreased BMI in midlife were at increased risk, up to four decades later. Gaining weight reduced the risk in our analyses. Why weight loss is related to dementia is poorly understood, and there is an ongoing discussion on this issue. Reverse causality has been suggested, especially in studies where BMI is measured in old age. Our study members were measured at baseline when they were 35-49 years and then followed up five-13 years later for a second BMI measurement at ages 40-62 years. We argued our results were less prone to reverse causality due to young age and very long follow-up time (as long as 35 years follow-up time after the second BMI measure), but we cannot rule it out even in this fairly young population. This new paper, using Mendelian randomization, strongly supports reverse causality as the main driver linking low weight with AD.

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Did low weight bring on the disease? The authors picked five genes that have been shown to have the strongest effects on body mass ... They reasoned that any linkage between variants that keep people slim and Alzheimer’s disease would support a causal effect of low BMI. Such Mendelian randomization studies approximate a randomized clinical trial, ...

In contrast to the observational data, common genetic variants that lead to low, or even high, BMI did not budge the risk of AD. To confirm BMI has no effect, the authors also analyzed data from two large genetic consortia, the Genetic Investigation of Anthropometric Traits (GIANT) and the International Genomics of Alzheimer’s Project (IGAP), which together comprise 303,958 participants. In these cohorts, the researchers looked at 32 genetic variants that influence body mass, and again saw no relationship to Alzheimer’s.

I do not find this a convincing argument at all. Imagine a scenario in which a BMI that is the result of genetic variants (low or high) is NOT associated with AD one way or another - yes, this is what the claim is. But what if a BMI that is the result of genetic variants is not associated with AD, but any BMI that is NOT the result of a genetic variant predisposition IS associated with AD? For example, let's say that you have no variant associated with BMI, but have low BMI due to, say, exercise and CR - what if that causes or is associated with AD? Clearly the study that shows BMI genetic variants not associated with AD is irrelevant as to whether BMI caused by anything OTHER than genetic variants might or might not cause or be associated with AD. In other words, this study does not disprove a hypothesis that keeping a low BMI with exercise and CR in the absence of BMI associated genetic variants causes AD. Therefore that study does NOT establlish anything of the kind as they claim. Just because BMI due to genetic variants is not associated with AD, does not mean that non-genetic BMI might still not be associated with AD.

Edited May 30, 2017 by TomBAvoider

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But, on the other hand, I see no evidence that, for, example, given two people with, say, identical genetic profiles (e.g., identical twins), the one with the higher or lower BMI would be more or less likely to develop Alzheimers than the other.

Disclaimer: Fortunately, I have no relations whoever had Alzheimers, or any other form of dementia.

-- Saul

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Agreed. However, there is some kind of statistical correlation of BMI and AD, and the point is in trying to determine of BMI is in some way causative. The argument about genetic variants and BMI was supposed to establish that BMI is not causative, all I'm saying is that this argument is not convincing. As to whether BMI is in fact causative or not, I suspect not, but I have no evidence.

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Did low weight bring on the disease? The authors picked five genes that have been shown to have the strongest effects on body mass ... They reasoned that any linkage between variants that keep people slim and Alzheimer’s disease would support a causal effect of low BMI. Such Mendelian randomization studies approximate a randomized clinical trial, ...

In contrast to the observational data, common genetic variants that lead to low, or even high, BMI did not budge the risk of AD. To confirm BMI has no effect, the authors also analyzed data from two large genetic consortia, the Genetic Investigation of Anthropometric Traits (GIANT) and the International Genomics of Alzheimer’s Project (IGAP), which together comprise 303,958 participants. In these cohorts, the researchers looked at 32 genetic variants that influence body mass, and again saw no relationship to Alzheimer’s.

I do not find this a convincing argument at all. ... what if a BMI that is the result of genetic variants is not associated with AD, but any BMI that is NOT the result of a genetic variant predisposition IS associated with AD? For example, let's say that you have no variant associated with BMI, but have low BMI due to, say, exercise and CR - what if that causes or is associated with AD? Clearly the study that shows BMI genetic variants not associated with AD is irrelevant as to whether BMI caused by anything OTHER than genetic variants might or might not cause or be associated with AD. In other words, this study does not disprove a hypothesis that keeping a low BMI with exercise and CR in the absence of BMI associated genetic variants causes AD. Therefore that study does NOT establlish anything of the kind as they claim. Just because BMI due to genetic variants is not associated with AD, does not mean that non-genetic BMI might still not be associated with AD.

I would agree with this line of argument if it were only one gene, as you could imagine that there might be some peculiar thing about this means of gaining fat that would not be linked to AD. But when you hve multiple genes that all relate to fat gain or resistance, and none of them are linked to AD positively or negatively, then the implication is pretty good that there's unlikely to be something about fat gain in and of itself that predisposes to AD.

But this really is more relevant to the question of the causal relationship between obesity and AD. The more relevant studies for looking at low BMI are the other ones referenced in the story, which are consistent with the view that the link observed between low BMI and AD is likely due to the prodromal stage of the disease process than low BMI causing AD. After all, absence of these "obesogenic" SNPs does not make one very thin — it just doesn't predispose you to becoming very overweight.